This invention relates to the preparation of pteridine compounds.
The folic acid antimetabolites N-[4-[[(2,4-diamino-6-pteridinyl)-methyl]amino]benzoyl]-L-glutamic acid (aminopterin) and N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamic acid (methotrexate) were synthesized nearly thirty years ago. Although aminopterin has been used as a folic acid antagonist in the treatment of leukemia and remains of interest for use as a rodenticide, it has not become as important in cancer chemotherapy as methotrexate, which has been in extensive clinical use for over 20 years. Methotrexate has become even more prominent in recent years through its use in newly developed clinical procedures involving its administration in massive doses followed by treatment with citrovorum factor. The use of methotrexate in this manner has greatly increased demands for production.
The usefulness of aminopterin and methotrexate as anticancer agents prompted a still-continuing search for structural variants, analogs, or derivatives that afford greater overall effectiveness. Drawbacks and limitations in available processes for preparing compounds structurally related to these antimetabolites by the common feature of the (2,4-diamino-6-pteridinyl)methyl grouping (unsubstituted at the 7-position) have caused many investigators to seek new synthetic approaches. The improvements needed in order to increase the attainable types and numbers of related compounds are greater versatility, percentage yields, and ease of purification of the products.